The Sharpless aminohydroxylation reaction (also known as the Sharpless oxyamination reaction), first published in 1975 (Sharpless, K. B.; Patrick, D. W.; Truesdale, L. K.; Biller, S. A., J. Am. Chem. Soc. 1975, 97, 2305-2307), and the Sharpless asymmetric aminohydroxylation reaction, first published in 1996 (Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl., 1996, 35, 451-453), allow the formation of a vicinal amino alcohol moiety from a simple alkene, in one step. The aminohydroxylation is effected by an osmium(VIII) complex that most favourably is present in catalytic amounts. The vicinal amino alcohol moiety is present in many biologically active compounds and these Sharpless aminohydroxylation reactions have therefore been used in many syntheses.
However, the aminohydroxylation reaction, while useful, is not without its limitations. The aminohydroxylation reaction requires a nitrogen source reagent, such as an amide, a sulfonamide or a carbamate. Carbamates have been widely used, but the reaction conditions typically involve the use of t-butyl hypochlorite in the presence of sodium hydroxide to produce an N-halocarbamate salt in situ, which is then used in the reaction. Such N-halocarbamate reagents can be unstable and difficult to store. In addition, the presence of base is an issue where base-sensitive substrates are being used. Further, the t-butyl hypochlorite has to be prepared prior to use by reaction of aqueous sodium hypochlorite, t-butanol and acetic acid, and used in reduced lighting as it is sensitive to photodecomposition.
Donohoe et al. have reported “tethered” (intramolecular) aminohydroxylation reactions, which can be carried out under “base-free” reaction conditions (Donohoe, T. J.; Chughtai, M. J.; Klauber, D. J.; Griffin, D.; Cambell, A. D. J. Am. Chem. Soc. 2006, 128, 2514-2515; Donohoe, T. J.; Bataille, C. J. R.; Gattrell, W.; Kloesges, J.; Rossignol, E. Org. Lett. 2007, 9, 1725-1728). However, yields for these reactions can be variable. The tethered reactions operate in a stereospecific fashion which means that they are not suited for use in the synthesis of compounds where certain stereochemistries may be desired.
Klauber et al. have reported the intermolecular aminohydroxylation of an alkene using the N-acyloxycarbamate (i):
as a nitrogen source (Klauber D. J., Donohoe T. J., Chughtai M. J. and Campbell A. D., 232nd ACS National Conference, September 2006; Klauber D. J., PhD Thesis, Oxford University). However, this reaction was optimally carried out under basic conditions (LiOH, 1.32 equivalents), which, as discussed above, are not desirable in situations where base-sensitive substrates are being used.
While investigating the total synthesis of the natural product allosamidin the applicant encountered some issues when using the aminohydroxylation reaction to prepare a key intermediate in the process. The substrate for that aminohydroxylation reaction has base-sensitive substituents, and the tethered aminohydroxylation reaction is not an option in this case, so using published methods results in only limited success.
Facile routes to the synthesis of biologically active compounds such as allosamindin are needed. The applicant has now found that the aminohydroxylation of alkenes can be achieved in a reliable manner and frequently in high yield using N-oxycarbamate compounds as nitrogen source reagents, and that the reaction can be carried out under “base-free” conditions.
It is therefore an object of the present invention to provide a process for the aminohydroxylation of alkenes, or to at least provide a useful choice. It is another object of the invention to provide nitrogen source reagents for the aminohydroxylation reaction, or to at least provide a useful choice.